DNMT3B PWWP mutations cause hypermethylation of heterochromatin.

Autor:	Taglini F; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.; CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK., Kafetzopoulos I; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.; CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.; Altos Labs, Cambridge Institute, Cambridge, UK., Rolls W; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.; Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK., Musialik KI; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.; CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.; MRC London Institute of Medical Sciences and Institute of Clinical Sciences, Imperial College London, London, UK., Lee HY; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.; CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.; Endocrine Oncology Research Group, Department of Surgery, The Royal College of Surgeons RCSI, University of Medicine and Health Sciences, Dublin, Ireland., Zhang Y; Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK., Marenda M; IEO, European Institute of Oncology IRCCS, Department of Experimental Oncology, Milan, Italy., Kerr L; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.; Department of Mathematics and Statistics, University of Strathclyde, Glasgow, UK., Finan H; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.; CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.; Swiss Federal Institute of Technology, ETH Zürich, Institute of Molecular Health Sciences, Zürich, Switzerland., Rubio-Ramon C; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.; CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.; Université Paris Cité, CNRS, Institut Jacques Monod, Paris, France., Gautier P; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK., Wapenaar H; Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK., Kumar D; Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK., Davidson-Smith H; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK., Wills J; CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK., Murphy LC; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK., Wheeler A; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK., Wilson MD; Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK. Marcus.Wilson@ed.ac.uk., Sproul D; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK. d.sproul@ed.ac.uk.; CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK. d.sproul@ed.ac.uk.
Jazyk:	angličtina
Zdroj:	EMBO reports [EMBO Rep] 2024 Mar; Vol. 25 (3), pp. 1130-1155. Date of Electronic Publication: 2024 Jan 30.
DOI:	10.1038/s44319-024-00061-5
Abstrakt:	The correct establishment of DNA methylation patterns is vital for mammalian development and is achieved by the de novo DNA methyltransferases DNMT3A and DNMT3B. DNMT3B localises to H3K36me3 at actively transcribing gene bodies via its PWWP domain. It also functions at heterochromatin through an unknown recruitment mechanism. Here, we find that knockout of DNMT3B causes loss of methylation predominantly at H3K9me3-marked heterochromatin and that DNMT3B PWWP domain mutations or deletion result in striking increases of methylation in H3K9me3-marked heterochromatin. Removal of the N-terminal region of DNMT3B affects its ability to methylate H3K9me3-marked regions. This region of DNMT3B directly interacts with HP1α and facilitates the bridging of DNMT3B with H3K9me3-marked nucleosomes in vitro. Our results suggest that DNMT3B is recruited to H3K9me3-marked heterochromatin in a PWWP-independent manner that is facilitated by the protein's N-terminal region through an interaction with a key heterochromatin protein. More generally, we suggest that DNMT3B plays a role in DNA methylation homeostasis at heterochromatin, a process which is disrupted in cancer, aging and Immunodeficiency, Centromeric Instability and Facial Anomalies (ICF) syndrome. (© 2024. The Author(s).)
Databáze:	MEDLINE
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